PROJECT SUMMARY Prevalent, morbid, and costly (>$20 billion/year in 2000), incontinence is a major problem, especially for older adults, in whom the most common type is urgency urinary incontinence (UUI). Ascribed to bladder spasms, UUI's causes are unknown, and therapy remains inadequate. Recent data suggest that one cause is poor bladder control by the brain. In our recent R01 we used biofeedback (BFB) as a probe to explore this. The exciting findings suggest that there are ? 2 brain (pheno)types of UUI; that they respond differently to BFB, and via different mechanisms; and that their response can be predicted. The new study will extend this work to examine mechanisms of drug treatments to identify potentially new targets for therapy. Data suggest that bladder control comprises 3 cerebral circuits which maintain continence by suppressing the voiding reflex in the midbrain. In the phenotype that responded to BFB, the mechanism involved enhancing deactivation of the first brain circuit (medial prefrontal cortex, mPFC) which resulted in less activation of the second circuit (which includes the midcingulate cortex). In the phenotype that was resistant to BFB, no brain changes were seen. Yet, BFB is used less often than drugs to treat UUI. The mechanism(s) that mediate drug response are unknown but likely involve changes in afferent activity ascending to the brain. The proposed study would be the first to address this critical knowledge gap. It is based not only on insights generated from our BFB study, but also on a pilot study of the bladder relaxant fesoterodine and our working model of brain/bladder control. Our overall aim is to use fesoterodine as a probe, to improve our understanding of the brain's role in UUI and identify new targets for therapy. Specific aims are to: (1) test whether efficacy of drug therapy varies by brain phenotype (the two identified in our BFB study or others that this study will identify); (2) confirm that mPFC deactivation is a key therapeutic mechanism, regardless of intervention; (3) determine if drug therapy normalizes brain response as a non-specific reaction to therapy; and (4) use newer MRI techniques to extend our current methods and thereby confirm or refute our model of brain/bladder control. To address these aims, we will randomize 150 women aged ? 60 years to receive 12 weeks of either fesoter- odine or placebo and then switch then to the alternate therapy for another 12 weeks. The study will enable us to correlate the change in CNS activation/deactivation with clinical response to therapy and also to discern whether CNS changes revert as incontinence worsens following withdrawal of therapy (on placebo) and to identify brain predictors and mechanisms of response. This study will provide the first ever data on brain mechanisms involved in UUI response to a drug. Regardless of the results, it will contribute substantially to current understanding and should facilitate development of better targeted therapy.